1,1-Disubstituted-2-alkyl 3-oxo-isoindolines

ABSTRACT

1,1-disubstituted-2-alkyl isoindolines, e.g. 1,1-diphenyl-2methyl isoindoline, are prepared by treating a corresponding isoindolinone with mild reducing agent. The compounds are useful as analgesics.

United States Patent 191 Houlihan et al.

[ 1 l,l-DlSUBSTlTUTED-Z-ALKYL S-OXO-ISOINDOLINES [75] Inventors: WilliamJ. Houlihan, Mountain Lakes; Jeffrey Nadelson, Parsippany. both of NJ.

[73] Assignee: Sandoz-Wander, lnc., Hanover. NJ.

[22] Filed: Mar. 12, 1973 [21] Appl. No.: 340,239

Related US. Application Data [62] Division of Ser. No. 74,467, Sept. 22,i970. Pat. No.

[52] US. Cl....260/325 PH; 260/326.1; 260/346.2 R;

260/559 R; 424/274 [51] Int. Cl C07d 27/50 Apr. 22, 1975 [58] Field ofSearch 260/325 [56] References Cited OTHER PUBLICATIONS Collington etal. J. Chem. Soc.. (c); 1968, 1021-1025.

Primary E.\'aminer- Joseph A. Narcavage Attorney, Agent, or F irmGeraldD. Sharkin; Robe S. Honor 1 3 Claims, No Drawings1,l-DISUBSTITUTED-Z-ALKYL S-OXO-ISOINDOLINES This is a division ofapplication Ser. No. 74,467 filed Sept. 22, 1970 now US. Pat. No.3,741,980.

This invention relates to isoindolines. More particularly, it relates tol-phenyl or substituted phenyll-aryl- 2-alkyl isoindolines, acidaddition salts and intermediates thereof, and processes for thepreparation of these materials.

The compounds of this invention may be represented by the followingstructural formula:

Ar 1 (I) R-N l 3 wherein R represents primary and secondary loweralkyl,i.e. primary and secondary alkyl having 1-5 carbon atoms such as methyl,ethyl, and isopropyl;

each R independently, represents hydrogen, halo having an atomic weightof 19 to 36, trifluoromethyl, loweralkoxy, i.e. alkoxy having 1 to 5carbon atoms, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy and the like or loweralkyl, i.e. alkyl having l-5 carbon atomssuch as methyl, ethyl, propyl, isopropyl and the like; or two of Rtogether represent methylenedioxy, provided they are on adjacent carbonatoms,

R represents hydrogen, trifluoromethyl, lower alkyl,

as previously defined, or lower alkoxy as previously R representshydrogen, halo having an atomic weight of 19 to 36, or lower alkoxy aspreviously defined; and

Ar represents phenyl, pyridyl (2,3 and 4), thienyl (2 and 3), and furyl(2and 3) and naphthyl (land 2);

provided no two trifluoromethyl groups are on adjacent carbon atoms,provided also that no more than three of R R and R are other thanhydrogen and that no more than two of R R and R are other than hydrogenin one ring.

The compounds of formula (I) may be prepared as represented by thefollowing reaction scheme:

mild reducing R agent wherein R, R,, R R and Ar and the provisos havethe above-stated significance. According to this aspect of theinvention, the com- 5 pounds of formula (1) are prepared by reducing acompound of formula (ll) with a mild reducing agent, particularly metalhydride, e.g. lithium aluminum hydride, diisobutylaluminum hydride,diborane, or sodium bis- (2-methoxyethoxy) aluminum hydride, in inertsolvent and insert atmosphere, e.g. nitrogen gas, at a temperature offrom about l0C. to 150C, conveniently at the reflux temperature of thesystem, for about 15 to 48 hours, preferably about 18 to 24 hours.Solvents which may be used include ethers such as ethyl ether ortetrahydrofuran, or hydrocarbon solvents such as benzene, toluene andthe like. The temperature, reaction times and solvents used are notcritical. The compounds of formula (I) may be recovered usingconventional recovery techniques such as crystallization.

The compounds of formula (ll), a further aspect of this invention, maybe prepared according to the following reaction scheme:

(III) wherein R, R R R Ar and the provisos have the abovestatedsignificance.

Compounds (11) are prepared by treating compounds (11]) with strongmineral acid such as hydrohalic acid, e.g. hydrochloric acid, at about40l00C, conveniently at the reflux temperature of the system, for about12-24 hours. Neither the reaction time nor temperature are critical, andsolvent is not required. The compounds (1]) are then recovered usingconventional techniques, e.g., filtration and recrystallization.

The compounds (Ill) are prepared according to the following reactionscheme:

The compounds of formula (III) are prepared by cyclizing a compound offormula (IV) inan aqueous or non-aqueous media with mineral acid, suchas sulfuric acid,'a hydrohalic acid such as hydrochloric or hyd'robromicacid, phosphoric acid and the like, at a temperature of from about 70 to120C'., conveniently at the reflux temperature of the system;-Morepreferably, and

for generally improved yields, the compounds'(lll) may be prepared fromcompounds of formula (IV) by treatment'with organic acids or theiranhydrides, such as acetic acid, trifluoroacetic acid, acetic acidanhydride, trifluoroacetic acid anhydride and the like,.at a temperoraqueous solutions normally used for hydrolysis, e.g.,

ature of about to +10C., preferably 5 to +5C:.v

The anhydrides are preferred and trifluoroacetic acid anhydride is aparticularly preferred cyclizing agent.

The reaction-is suitably conducted for about 1-48 hours, preferably24-48 hours for the mineral acids and of the compounds (Ill). Toimproveyields and obtain.

a better quality product, the reaction may be :performed under inertatmosphere, e.g. nitrogen gas. Neither the time nor temperature ofreaction is critical. Compounds (Ill) may be recovered usingconventional recovery techniques, such as filtration.

The compounds (III) are novel except in that instance where Arrepresents phenyl, R represents methyl and all other variablesubstituents represent hydrogen,

According to a still further aspect of this invention, compounds (IV);new and novel except where Ar is phenyl, R is methyl and all othersubstituents are hydrogen, may be] prepared as illustrated in thefollowing reactionscheme from compounds (V) and (VI).

l /AI R-l1 1 Li 0 l R a o J R .1

.1. l l 'l Ar l l I 11 I R-N R 2 0 R3 (IV) where R, R R R Ar and theprovisos have the above stated significance.

Compounds (IV) may be prepared by condensing a compound (V) with acompound (VI) in an inert solvent such as ether, e.g. diethyl ether ortetrahydrofuran, or hydrocarbons or aromatic hydrocarbons such ashexane, heptane, benzene, toluene and the like. This condensation may becarried out at a temperature of ammonium chloride solution, at about 0to 10C. The

'product may then be used directly for the preparation .of compounds(III).

It will be understood that certain of the compounds of formulas (I),(II), (III) and (V) exist in racemic form or in the form of opticallyactive isomers. The separation of the respective isomers may beaccomplished employing conventional techniques and such isomers areincluded within the scope of the invention.

Certain of the compounds of formulas (V) and (VI) are known and may beprepared by methods described in 'the literature. Those compounds offormulas (V) and (VI) not specifically described may be prepared byanalogous methods from known materials.

The compounds of formula (I) are useful because they possesspharmacological activity in animals, such as mamals. In particular, thecompounds possess analgesic activity as indicated by their activity inmice at 25 mg/kg orally when tested using the Hot-Platemethod of Woolfeand McDonald (J. Pharmacol. & Exper. Therap. :300, 1944).

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carriers or adjuvants. Depending upon theparticular active compound employed, the exact dosage utilized may vary.

Furthermore, the compounds of formula (I) may be similarly administeredinthe form of their non-toxic pharmaceutically acceptable acid additionsalts. Such salts possess the same order of activity as the free base,are readily prepared by reacting the base with an appropriate acid andaccordingly are included within the scope'of the invention.Representative of such-salts are the mineral acid salts, such'as thehydrochloride, hydrobromide, sulfate, phosphate and the like and theorganic acid salts, such as the succinate, benzoate, acetate,p-toluenesulfonate, benzenesulfonate and the like.

lngeneral, satisfactory results are obtained when the compounds areadministered orally at a daily dosage of from about 0.1 mg/kg of animalbody weight, preferably given in divided doses, 2 to 4 times a day or insustained release form. For most larger mammals (e.g., primates) thetotal daily dosage is from about 5 milligrams to about 400 milligrams.Dosage forms suitable for internal use comprise from about 1.5milligrams to about 200 milligrams of the active compound in intimateadmixture witha solid or liquid pharmaceutically acceptable carrier ordiluent.

A representative formulation suitable for oral administration is acapsule prepared by standard techniques which contains the followingIngredients: Parts by weight:

1.1-diphenyl-2-methyl isoindolinc 25 Inert filler (starch. kaolin,lactose. 275

etc.)

for a particular isomer and in such instances administration of suchisomer may be preferred.

The preferred compounds of formula (I) are those wherein Ar, R and R, onthe isoindoline moiety are as previously defined and all othersubstituents represent hydrogen.

The corresponding compounds of formulae (ll), (Ill) and (V1) aresimilarly preferred.

EXAMPLE 1 (1,04-Diphenyl-a-hydroxy-N-methyl-o-toluamide To a flaskequipped with a stirrer, dropping funnel, condenser and gas inlet tubemaintained under a nitrogen atmosphere there is added at roomtemperature 15.2 g. (0.018 mole) of N-methyl benzamide and 150 ml. ofdry tetrahydrofuran. The reaction flask is immersed in an ice bath'andcooled to an internal temperature of 5C. Stirring is initiated and 152m]. of 1.6 M n-butyllithium (0.24 mole) in hexane is added dropwise inca 1 hour maintaining the temperature below 8C. The resulting dilith iosalt is stirred at 5C. for an additional hour and then a solution of19.6 g (0.108 mole) of benzophenone in 75 ml. of anhydroustetrahydrofuran is added dropwise in ca 45 min. maintaining thetemperature between "10 and 10C. The resulting mixture is stirred at 5C.for 1 hour longer and then poured with stirring onto 300 g. of ice whilemaintaining the temperature below 10C. The layers are separated, thetetrahydrofuran layer fried over anhydrous magnesium, sulfate, andfiltered and evaporated in vacuo. The resulting oil is triturated withcold ethyl ether and filtered to give crudea,a-diphenyl-ahydroxy-N-methyl-o-toluamide.

When the above process is carried out and m-methyl benzophenone,

. phenyl-Z-pyridylketone,

. p-methoxyphenyl-2thienylketone,

. p-chlorophenyl-3-furylketone,

. Z-naphthyl p-trifluoromethylphenylketone, or

3,4-methylenedioxy benzophenone sed in place of benzophenone, there isobtained a--hydroxy-a-phenyl-a-( m-tolyl )-N-methyl-otoluamide, Y

b. a-hydroxy-a-phenyl-a-(2-pyridyl)-N-methyl-otoluamide,

c. a-hydroxy-a-(p-methoxyphenyl)-a-(2-thienyl)-N- methyl-o-toluamide,

a-hydroxy-a-(p-chlorophenyl)-u-(3-furyl)-N- methyl-o-toluamide,

e.a-hydroxy-a-(2-naphthyl)-a-(ptrifluoromethylphenyl)-N-methyl-o-toluamide,or

f. a-hydroxy-z(3,4-methylenedioxyphenyl)-aphenyl-N-methyl-o-toluamide,respectively.

When the above process is carried out and o-chloro- N-methyl benzamideor N-ethyl-m-methoxy benzamide is used in place of N-methyl benzamide,there is obtained 6-chloro-a,a-diphenyl-a-hydroxy-N-methyl-2- toluamide,or a,a-diphenyl-a-hydroxy--methoxy-N- ethyl-2-toluamide, respectively.

EXAMPLE 2 3,3-Diphenyl-l-methy1imino phthalan To a flask equipped with astirrer, condenser and gas inlet tube maintained under a nitrogenatmosphere there is added at room temperature 100 g. of trifluoroaceticacid anhydride. The flask is cooled to an internal temperature of 0C,and 20 g. of the crude a,a-diphenyl-a-hydroxy-N:methyl-o-toluamideobtained in Example 1 is added in portions with stirring. The reactionmixture is maintained at0C. for 1 hour, at room temperature for 18hours, and is then evaporated in vacuo. The residue is dissolved inmethylene chloride and washed with ml. of water, 100 ml. of 2N sodiumhydroxide and again 100 ml. of water, dried over magnesium sulfate,filtered and evaporated in vacuo. The resulting solid is triturated withcold ethyl ether and the ether insoluble material is recrystallized fromhot ethyl acetate to give 3,3-diphenyl-l-methylimino phthalan.

When the above procedure is carried out and a. a-hydroxy---a-phenyl-a(m-tolyl)-N-methyl-o-toluamide,

a-hydroxy-a-phenyl-a(2-pyridyl)-N-methyl-otoluamide, c.a-hydroxy-a-(p-methoxyphenyl(-a-(2-thienyl)-N- methyl-o-toluamide,

a-hydroxy-- -a-(p-chlorophenyl-a-(3-fury1 )-N-methyl-otoluamide, a

e a-hydroxy-a-(Z-naphthyl)-a(ptrifluoromethylphenyl)-N-methyl-o-to1uamide, f. a-hydroxy-a( 3,4-methylenedioxyphenyl )-aphenyl-N v t g.6-chloro-a,a-diphenyl-a-hydroxy-N-methyl-2- toluamide, or

a,a-diphenyl-a-hydroxy-5-methoxy-N-ethyl 2- toluamide a is used in placeof a,a-diphenyl-a-hydroxy-N-methyl-otoluamide, there is obtained a.l-methylimino-3-phenyl-3-(m-tolyl)phthalan, b.1-methylimino-3Tphenyl-3(2-pyridyl)phthalan, d.3-,(p-chlorophenyl)-3-(3furyl)-l-methylimino phthalan, y e.1-methylimino-3-(Z-naphtyl)-3-(p trifluoromethylph enyl)phthalan, f.l-methylimino-3-( 3,4-methylenedioxyphe'nyl)-3- phenyl phthalan, g.5-chloro-3,3-diphenyl-l-methyliminophthalan,'or h.3,3-diphenyl-l-ethylimino-o-methoxy phthalan,

respectively. 5, H

7 EXAMPLE 3 I l,l-Diphenyl-2-methyl isoindoline-3-one A mixture of 36.7gQof 3,3-diphenyl-l-methylimino phthalanand 400 m1. of 2N hydrochloricacid is heated at reflux for 18 hours. The mixture is then cooled andfiltered, and the resulting solid is'washed with water, dissolved inmethylene chloride and dried with magnesium sulfate. The solution isthen filtered, evaporated and the resulting solid is recrystallized fromhot ethyl acetate to give 1,1-diphenyl-2-methyl isoindoline- 3-one.

When the above procedure is used and in place of3,3-diphenyl-l-methylimino phthalan there is used a. l-methylimino-3-3(m tolyl)phthalah';

b. 1-methylimino-3-phenyl-3-( 2-pyridyl)phthalan,

c. 3-(p-methoxyphenyl)-l-methylimino-3-(2- thienyl)phthalan,

3-(p-chlorlphenyl)-3-(3-furyl)-1-methylimino phthalan, e.l-methylimino-3-(2-naphyl)-3-(p-trifluoromethylphenyl)phthalan, f.l-methylimino-3-(3,4-methylenedioxyphenyl) 3- phenyl phthalan,

or h. l, l -diphenyl-2-ethyl-5-methoxy isoindoline-3-one,

respectively.

EXAMPLE 4 l, l -Diphenyl-2-methyl isoindoline To a flask equipped with astirrer, condenser, and gas inlet tube maintained under a nitrogenatmosphere there is added at room temperature 1.14 g. (0.03 mole) oflithium aluminum hydride and 50 ml. of anhydrous tetrahydrofuran.Stirring is initiated and a solution of 6.3 g. (0.021 mole) ofl,l-diphenyl-2-methyl isoindoline-3-one in 120 ml. of anhydroustetrahydrofuran is added dropwise in ca. 30 minutes. The resultingmixture is refluxed for 18 hours and cooled in an ice bath. Ethylacetate(6.8 ml) is added dropwise in ca. 10 minutes. followed by the dropwiseaddition of 2.3 ml. of 2N of sodium hydroxide in ca. 10 minutes and thedropwise addition of 3.4 ml. of water in ca. 10 minutes. The resultingmixture is dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo to give a semisolid which is triturated with hotether. The filtrate is evaporated in vacuo and the residuerecrystallized from pet. ether to give l,l-diphenyl-2-methylisoindoline; m.p. l02l04.5C.

When the above process is carried out and in place ofLl-diphenyl-Z-methyl isoindoline-3-one there is useda.Z-methyl-l-phenyl-l-(m-tolyl)isoindoline-3-one,

b. Z-methyI-I-phenyl-l-(Z-pyridyl)isoindoline-3-one,

c. l-(p-methoxyphenyl)-2-methyl-l-(2-thienyl)isoindoline-3-one,

d. l-(p-chlorophenyl)-l-(3-furyl)-2-methyl isoindoline-3-one,

e. 2-methyl-l-(2-naphthyl)-l-(optrifluoromethylphenyl)isoindoline-3-one,

f. Z-methyl-l(3,4-methylenedioxyphenyl)-l-phenyl isoindoline-3-one,

g. 6-chloro-.l,l-diphenyl-2-methyl isoindoline-3-one,

h. 1,l-diphenyl-2-ethyl-5-methoxy isoindoline'3-one, there is obtaineda. Z-methyl-l-phenyl-l-(m-tolyl)isoindoline,

b. 2-methyl--l-phenyl-l-(2-pyridyl)isoindoline,

c. l-(p-methoxyphenyl)-2-- -methyl-l-(2-thienyl)isoindoline,

d. l1-(p-chIorphenyl)-l-(3-furyl)-2-methyl isoindoline,

e. Z-methyl-l ((Z-naphthyl l (p-trifluoromethylphenyl)isoindoline,

f. 2-methyl-l-(3,4-methylenedioxyphenyl)-l-phenyl isoindoline,

g. 6-chloro-l,l-diphenyl-Z-methyl isoindoline, or

h. l,l-diphenyl-2-ethyl-5-methoxy isoindoline, re-

spectively.

10 What is claimed is:

l. A compound of the formula wherein 5 R'represents primary andsecondary lower alkyl.

each R independently, represents hydrogen, halo having an atomic weightof 19 to 36, trifluoromethyl, lower alkoxy or lower alkyl; or two of R,together represent methylenedioxy, provided they are on adjacent carbonatoms;

R represents hydrogen, trifluoromethyl, loweralkoxy or lower alkyl; Rrepresents hydrogen, halo having an atomic weight of 19-36, or loweralkoxy; and Ar represents phenyl, pyridyl, thienyl, furyl or naphthyl;provided no two trifluoromethyl groups are on adjacent carbon atoms,provided also that no more than three of R R and R are other thanhydrogen, and that no more than two of R R and R are other than hydrogenin one ring, or a pharmaceutically acceptacle acid addition saltthereof. 2. A compound according to claim 1 which is l, l-diphenyl-2-methyl isoindoline-3-one. 3. A compound of the formula whereR, R and Ar are as defined in claim 1. 6O a:

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compoundaccording to claim 1 which is 1,1-diphenyl-2-methyl isoindoline-3-one.